FBXW7在非小细胞肺癌治疗耐药中的研究进展

Research progress in the role of FBXW7 in drug resistance against non-small cell lung cancer

非小细胞肺癌(non-small cell lung cancer,NSCLC)是全球范围内最常见的恶性肿瘤之一。NSCLC治疗耐药严重影响了预后,研究NSCLC治疗耐药的分子机制非常必要。泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)能够通过选择性降解短期蛋白调节细胞内重要过程,如周期调控、转录调控、信号转导、凋亡和分化等,其表达的异常影响肿瘤的发生、发展及预后。F-box家族蛋白是UPS的重要组成部分,而F框/WD-40域蛋白7(F-box and WD-40 domain protein 7,FBXW7)是F-box家族蛋白中研究的经典蛋白之一。研究表明FBXW7与NSCLC耐药有关,主要机制是FBXW7突变减少其下游蛋白的泛素化降解,导致NSCLC患者药物治疗耐药,其下游蛋白包括Snail蛋白、骨髓细胞白血病因子1(myeloid cell leukemia sequence 1,MCL-1)、雷帕霉素靶蛋白(mammalian target of rapamycin,m TOR)、卷曲螺旋结构域6(coiled-coil-domain containing 6,CCDC6)。雷帕霉素、组蛋白脱乙酰酶抑制剂MS-275及冬凌草素对治疗耐药的FBXW7突变的NSCLC患者有效。

Non-small cell lung cancer (NSCLC) is one of the most common malignant tumors in the world. NSCLC shows serious effect on prognosis for drug resistance, and it is necessary to study the molecular mechanism for drug resistance in NSCLC. Ubiquitin-proteasome system (UPS) can regulate some important cellular processes by degrading short-term protein, and the abnormal expression is closely related to the occurrence, development and prognosis of tumor. The F-box family protein is an important component of the ubiquitin proteasome, such as cycle regulation, transcriptional regulation, signal transduction, apoptosis and differentiation. F-box and WD-40 domain protein 7 (FBXW7) is just the classic protein components among F-box family protein.Studies have shown that FBXW7 is related to drug resistance in NSCLC. The main mechanism is that FBXW7 mutation leads to drug resistance by reducing ubiquitination and degradation of its downstream proteins, including Snail protein, myeloid cell leukemia sequence 1 (MCL- 1), mammalian target of rapamycin (mTOR), and coiled-coil-domain containing 6 (CCDC6). Rapamycin, histone deacetylase inhibitor MS-275, and rabdosia are effective in drug-resistant NSCLC patients with FBXW7 mutation.